Adhesive peel-forming formulations for dermal delivery of drugs and methods of using the same

ABSTRACT

The present invention is drawn to adhesive peel-forming formulations for dermal delivery of a drug. The formulation can include a drug, a solvent vehicle, and a peel-forming agent. The solvent vehicle can include a volatile solvent system having one or more volatile solvent, and a non-volatile solvent system having one or more non-volatile solvent, wherein the non-volatile solvent system has a solubility for the drug that is within a window of operable solubility for the drug such that the drug can be delivered at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system. When applied to the skin, the formulation can form a solidified peelable layer after at least a portion of the volatile solvent system is evaporated.

The present application claims the benefit of U.S. ProvisionalApplication No. 60/577,536, filed on Jun. 7, 2004, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to systems developed for dermaldelivery of drugs. More particularly, the present invention relates toadhesive peel-forming formulations having a viscosity suitable forapplication to a skin surface, and which form a sustaineddrug-delivering adhesive solidified peelable layer on the skin.

BACKGROUND OF THE INVENTION

Traditional dermal drug delivery systems can generally be classifiedinto two forms: semisolid formulations and dermal patch dosage forms.Semisolid formulations are available in a few different forms, includingointments, creams, pastes, gels, or lotions and are applied topically tothe skin. Dermal (including transdermal) patch dosage forms also areavailable in a few different forms, including matrix patchconfigurations and liquid reservoir patch configurations. In a matrixpatch, the active drug is mixed in an adhesive that is coated on abacking film. The drug-laced adhesive layer is typically directlyapplied onto the skin and serves both as means for affixing the patch tothe skin and as a solvent for the drug. Conversely, in a liquidreservoir patch, the drug is typically incorporated into a solventsystem which is held by a thin bag, which can be a thin flexiblecontainer. The thin bag can include a permeable or semi-permeablemembrane surface that is coated with an adhesive for affixing themembrane to the skin. The membrane is often referred to as a ratelimiting membrane (although it may not actually be rate limiting in thedelivery process in all cases) and can transfer the drug from within thethin bag to the skin for dermal delivery.

While patches and semisolid formulations are widely used to deliverdrugs into and through the skin, they both have significant limitations.For example, most semisolid formulations usually contain solvent(s),such as water and ethanol, which are volatile and thus evaporate shortlyafter application. The evaporation of such solvents can causesignificant decrease or even termination of dermal drug delivery, whichmay not be desirable in many cases. Additionally, semisolid formulationsare often “rubbed into” the skin, which does not necessarily mean thedrug formulation is actually delivered into the skin. Instead, thisphrase often means that a very thin layer of the drug formulation isapplied onto the surface of the skin. Such thin layers of traditionalsemisolid formulations applied to the skin may not contain sufficientquantity of active drug to achieve sustained delivery over long periodsof time. Additionally, traditional semisolid formulations are oftensubject to unintentional removal due to contact with objects such asclothing, which may compromise the sustained delivery and/or undesirablysoil clothing. Drugs present in a semisolid formulation may also beunintentionally delivered to persons who come in contact with a patientundergoing treatment with a topical semisolid formulation.

With respect to matrix patches, in order to be delivered appropriately,a drug should have sufficient solubility in the adhesive, as primarilyonly dissolved drug contributes to skin permeation driving force.Unfortunately, many drugs have solubility in adhesives that is not highenough to generate sufficient skin permeation driving force. Inaddition, many ingredients, e.g., liquid solvents and permeationenhancers, which could be used to help dissolve the drug or increase theskin permeability, may not be able to be incorporated into many adhesivematrix systems in sufficient quantities to be effective. For example, atfunctional levels, most of these materials can tend to adversely alterthe wear properties of the adhesive. As such, the selection andallowable quantities of additives, enhancers, excipients, or the like inadhesive-based matrix patches can be limiting. To illustrate, for manydrugs, optimal transdermal flux can be achieved when the drug isdissolved in certain liquid solvent systems, but a thin layer ofadhesive in a typical matrix patch often cannot hold enough appropriatedrug and/or additives to be therapeutically effective. Further, theproperties of the adhesives, such as coherence and tackiness, can alsobe significantly changed by the presence of liquid solvents.

Regarding liquid reservoir patches, even if a drug is compatible with aparticular liquid or semisolid solvent system carried by the thin bag ofthe patch, the solvent system still has to be compatible to the adhesivelayer coated on the permeable or semi-permeable membrane; otherwise thedrug may be adversely affected by the adhesive layer or the drug/solventsystem may reduce the tackiness of the adhesive layer. In addition tothese dosage form considerations, reservoir patches are bulkier andusually are more expensive to manufacture than matrix patches.

Another shortcoming of many patches is that they are usually neithersufficiently stretchable nor flexible, as the backing film (in matrixpatches) and the thin fluid bag (in reservoir patches) are typicallymade of relatively non-stretchable materials. If the patch is applied ona skin area that is significantly stretched during body movements, suchas a joint, separation between the patch and skin may occur, therebycompromising the delivery of the drug. In addition, a patch present on askin surface may hinder the expansion of the skin during body movementsand cause discomfort. For these additional reasons, patches are notideal dosage forms for skin areas subject to expansion and stretchduring body movements.

In view of the shortcomings of many of the current delivery systems, itwould be desirable to provide systems, formulations, and/or methods thatcan i) provide more sustained drug delivery over long periods of time;ii) are not vulnerable to unintentional removal by contact withclothing, other objects, or people for the duration of the applicationtime; iii) can be applied to a skin area subject to stretching andexpansion without causing discomfort or poor contact to skin; and/or iv)can be easily removed after application and use.

SUMMARY OF THE INVENTION

It has been recognized that it would be advantageous to provide dermaldelivery formulations, systems, and/or methods in the form of adhesivepeel-forming compositions or formulations having a viscosity suitablefor application to the skin surface and which form a drug-deliveringsolidified peelable layer on the skin that is easily peelable orremovable after use. In accordance with this, an adhesive peel-formingformulation for dermal delivery of a drug can comprise a drug, a solventvehicle, and a peel-forming agent. The solvent vehicle can comprise avolatile solvent system having one or more volatile solvent(s) and anon-volatile solvent system having one or more non-volatile solvent(s),wherein the non-volatile solvent system provides a window of operablesolubility for the drug such that the drug can be delivered intherapeutically effective amounts over a period of time, even after mostof the volatile solvent(s) is (are) evaporated. The formulation can haveviscosity suitable for application to the skin surface prior toevaporation of at least one volatile solvent, and can further beconfigured such that when applied to the skin surface, the formulationforms a solidified peelable layer after at least a portion of thevolatile solvent(s) is (are) evaporated.

In an alternative embodiment, a method of dermally delivering a drug toa subject can comprise applying an adhesive peel-forming formulation toa skin surface of the subject, dermally delivering the drug from thesolidified peelable layer over a period of time and at desired rates,and removing the solidified peelable layer from the skin after a periodof time has elapsed or the desired quantity of the drug has beendelivered. The adhesive peelable formulation can include a drug, asolvent vehicle, and a peel-forming agent. The solvent vehicle cancomprise a volatile solvent system having one or more volatilesolvent(s) and a non-volatile solvent system having one or morenon-volatile solvent(s), herein the non-volatile solvent system has asolubility for the drug that is within a window of operable solubilityfor the drug such that the drug can be delivered in therapeuticallyeffective amounts over a period of time, even after most of the volatilesolvent(s) is (are) evaporated. The formulation can have a viscositysuitable for application to a skin surface prior to evaporation of thevolatile solvent(s). When the formulation is applied to the skinsurface, the formulation can form a solidified peelable layer after atleast a portion of the volatile solvent system evaporated.

In another embodiment, a method of preparing an adhesive peelableformulation for dermal drug delivery can comprise steps of selecting adrug suitable for dermal delivery; selecting a non-volatile solventsystem consisting essentially of one non-volatile solvent that has asolubility with respect to the drug within a window of operablesolubility; and formulating the drug and the non-volatile solvent intoan adhesive peel-forming formulation. The adhesive peel-formingformulation can include a peel-forming agent and a volatile solventsystem including at least one volatile solvent. The adhesivepeel-forming formulation can have a viscosity suitable for applicationto a skin surface prior to evaporation of the volatile solvent system,and can be applied to the skin surface where it forms a solidifiedpeelable layer after at least a portion of the volatile solvent systemis evaporated. In this embodiment, the drug continues to be delivered ata therapeutically effective amount after the volatile solvent system issubstantially evaporated.

In another embodiment, a method of preparing an adhesive peel-formingformulation for dermal drug delivery can comprise steps of selecting adrug suitable for dermal delivery; forming a non-volatile solvent systemby selecting at least two non-volatile solvents according to a ratiothat positions the solubility of the drug within a window of operablesolubility with respect to the non-volatile solvent system; andformulating the drug and the non-volatile solvent system into anadhesive peel-forming formulation. The adhesive peel-forming formulationcan include a peel-forming agent and a volatile solvent system includingat least one volatile solvent. The adhesive peel-forming formulation canalso have a viscosity suitable for application to a skin surface priorto evaporation of the volatile solvent system, and can be applied to theskin surface where it forms a solidified peelable layer after at least aportion of the volatile solvent system is evaporated. The drug cancontinue to be delivered at a therapeutically effective amount after thevolatile solvent system is substantially evaporated.

In still another embodiment, a solidified peelable layer for deliveringa drug can comprise a drug, a non-volatile solvent system, and apeel-forming agent. The non-volatile solvent system can include one ormore non-volatile solvent(s), and can provide a window of operablesolubility for the drug such that the drug can be delivered in atherapeutically effective amount for at least 2 hours. Further, thepeelable layer can be stretched in at least one direction by 10% withoutbreaking, cracking, or separation from a skin surface to which thesolidified peelable layer is applied.

In still another embodiment, an adhesive peel-forming formulation fordermal delivery of a drug can comprise a drug, a peel-forming agent, anda solvent vehicle. The solvent vehicle can include a volatile solventsystem including one or more volatile solvent, a non-volatile solventsystem including one or more non-volatile solvent. After the adhesivepeel-forming formulation is applied to a skin surface, the adhesivepeel-forming formulation forms a solidified peelable layer having acontact surface having a first area dimension. The solidified peelablelayer can be stretchable such that the first area dimension is capableof being stretched to a second area dimension that is 10% larger thanthe first area dimension without cracking, breaking, and/or separatingfrom a skin surface to which the peel-forming formulation is applied.Further, after the formation of the solidified peelable layer and afterthe volatile solvent system is substantially evaporated, the drugcontinues to be delivered in therapeutically effective amounts.

Additional features and advantages of the invention will be apparentfrom the following detailed description and figures which illustrate, byway of example, features of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-4 are graphical representations of cumulative amount of a drugdelivered across a biological membrane in vitro over time from fourseparate solidified adhesive formulations in accordance with embodimentsof the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before particular embodiments of the present invention are disclosed anddescribed, it is to be understood that this invention is not limited tothe particular process and materials disclosed herein as such may varyto some degree. It is also to be understood that the terminology usedherein is used for the purpose of describing particular embodiments onlyand is not intended to be limiting, as the scope of the presentinvention will be defined only by the appended claims and equivalentsthereof.

In describing and claiming the present invention, the followingterminology will be used.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a drug” includes reference to one or more of such compositions.

As used herein, a plurality of drugs, compounds, and/or solvents may bepresented in a common list for convenience. However, these lists shouldbe construed as though each member of the list is individuallyidentified as a separate and unique member. Thus, no individual memberof such list should be construed as a de facto equivalent of any othermember of the same list solely based on their presentation in a commongroup without indications to the contrary.

“Skin” is defined to include human skin, finger and toe nail surfaces,and mucosal surfaces that are usually at least partially exposed to airsuch as lips, genital and anal mucosa, and nasal and oral mucosa.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 0.01 to 2.0 mm” should beinterpreted to include not only the explicitly recited values of about0.01 mm to about 2.0 mm, but also include individual values andsub-ranges within the indicated range. Thus, included in this numericalrange are individual values such as 0.5, 0.7, and 1.5, and sub-rangessuch as from 0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. This sameprinciple applies to ranges reciting only one numerical value.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

The phrase “effective amount,” “therapeutically effective amount,” or“therapeutically effective rate(s)” of a drug refers to a non-toxic, butsufficient amount or delivery rates of the drug, to achieve therapeuticresults in treating a condition for which the drug is being delivered.It is understood that various biological factors may affect the abilityof a substance to perform its intended task. Therefore, an “effectiveamount,” “therapeutically effective amount,” or “therapeuticallyeffective rate(s)” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a subjective decision. The determination of a therapeuticallyeffective amount or delivery rate is well within the ordinary skill inthe art of pharmaceutical sciences and medicine.

The phrases “dermal drug delivery” or “dermal delivery of drugs” shallinclude both transdermal and topical drug delivery, and shall mean thedelivery of drug(s) to, through, or into the skin. When transdermallydelivering the drug, skin, tissues just under the skin, regional tissuesor organs under the skin, systemic circulation, and/or the centralnervous system, for example, can be targeted.

The term “drug(s)” refers to any bioactive agent that is applied to,into, or through the skin which is applied for achieving a therapeuticaffect. This includes compositions that are traditionally identified asdrugs, as well other bioactive agents that are not always considered tobe “drugs” in the classic sense, e.g., peroxides, humectants,emollients, etc., but which can provide a therapeutic effect for certainconditions.

The term “window of operable solubility” refers to a solubility rangeprovided by a non-volatile solvent system for a selected drug. A drugsolubilized in a non-volatile solvent system with a solubility for thedrug within the window of operable solubility can provide acceptableskin permeation driving force, including optimal or near optimal dermalpermeation driving force. The appropriate selection or formulation ofthe non-volatile solvent system in the adhesive peelable formulations ofthe present invention is used to make sure that the solubility of thedrug is within the “window of operable solubility” which leads todesired dermal or transdermal delivery rates. In other words, in orderto achieve acceptable dermal delivery or transdermal flux/driving forceof a drug to or into a skin surface, drug solubility in the non-volatilesolvent system, which is the maximum amount of the drug that can bedissolved in a unit volume of the solvent system, should be within thiswindow of operable solubility, e.g., not overly soluble nor too poorlysoluble.

Generally, transdermal permeation driving force for a drug typicallyincreases by increasing drug concentration in a non-volatile solventsystem, until the solution is saturated. Conversely, for a given drugconcentration that is fully dissolved, the driving force usuallydecreases with increasing solubility or decreasing saturation. This canbe explained in accordance with certain physical chemistry principles,wherein a drug tends to stay in a solution in which it has bettersolubility. Stated another way, where a drug has good affinity with asolution (as reflected by high solubility), the drug will tend to stayin solution rather than venture outside of the solution and permeateinto the skin. Thus, low transdermal flux can be a result of not onlyinsufficient drug solubility in a non-volatile solvent system, but alsocan be a result of the drug being too “comfortable” (high drug-nonvolatile solvent affinity) within the non-volatile solvent system.Therefore, to achieve acceptable drug delivery, there exists a window ofoperable solubility for a given drug, and the solubility of the drug inthe non-volatile solvent system should be within this window in order toprovide sufficient or desired (which often, but not always means closeto maximum) transdermal driving force for the drug. This window ofoperable solubility is typically individualized for each drug. However,it is usually in the range of 0.01 wt % to 40 wt % of the adhesivepeelable formulation as a whole, and for many drugs, in the range of 0.5wt % to 20 wt %.

To illustrate this principle more fully, one can consider twoformulations, one having a non-volatile solvent system that is capableof dissolving 100 mg of a drug in each mL of solvent (solubility is 100mg/mL) and another having a non-volatile solvent system with thesolubility for the same drug at 6 mg/mL. If 5 mg of drug are placed in 1mL of each system, both would fully solubilize the drug, but the drivingforce of the drug in the 6 mg/mL non-volatile solvent system wouldtypically be much greater than the driving force provided by 100 mg/mLnon-volatile solvent system. In other words, even though the drug isfully dissolved in both systems, the drug would have better affinitywith the 100 mg/mL system and would thus provide a lower driving forcefor dermal permeation.

This is also supported by thermodynamics and diffusion concepts, wherethe “window of operable solubility” reflects a range of drug (solute)activities in a non-volatile solution that is needed for deliveringsufficient flux or amount of the drug across the skin or mucosalmembrane.

More quantitatively, the flux of permeation, defined as quantity of drugpermeated across a unit area of skin (typically one square centimeter)over a unit length of time (typically one hour), is given by:J=PC   (1)where C is the concentration of dissolved drug and P is the permeabilitycoefficient of the drug across the skin or mucosal membrane, and isindependent of drug concentration. P is dependent of the drug and theformulation, but, based on all data that the inventors are aware of, isusually not higher than 10⁻⁵ cm/sec for even a well optimizedtransdermal drug delivery system.

Equation (1) and the observed cap of P suggest that sufficient fluxcannot be achieved if the drug concentration is too low. Since the drugconcentration is capped by the solubility of the drug in theformulation, this means the formulation has to have certain solubilityfor the drug in order to have sufficient flux.

Thus, Equations (1) supports the concept that that there exists a rangeof solubility outside of which the formulation will not yield desired oroperable dermal permeation driving force. The appropriate selectionand/or formulation of the non-volatile solvent system in the peelformulations is utilized in this invention to assure that the solubilityis within this “window of operable solubility” which leads to thedesired transdermal properties.

The phrase “substantially constant” when referring to “sustaineddelivery” of drug can be defined in terms of either an in vitropermeability across human or hairless mouse skin or epidermis, or by adata collected from a pool of 12 or more human subjects, wherein thedrop in mean drug delivery rate over a specified period of time (2 hoursor longer) is not more than 50% from a peak drug delivery rate. Thus,compositions that are delivered at a “substantially constant” rateinclude formulations that deliver a drug at substantially constant andtherapeutically significant rates for an sustained period of time, e.g.,2 hours, 4 hours, 8 hours, 12 hours, 24 hours, etc. The use ofnon-volatile solvent systems having a window of operable solubility asdefined previously can achieve this sustained delivery attherapeutically significant rates over sustained period of time.

“Volatile solvent system” can be a single solvent or a mixture ofsolvents that are volatile, including water and solvents that are morevolatile than water.

“Non-volatile solvent system” can be a single solvent or mixture ofsolvents that are less volatile than water. Most of the non-volatilesolvent system should remain in the solidified peelable layer aftervolatile solvent system evaporation for a time sufficient to dermallydelivery a given drug to, into, or through the skin of a subject at asufficient flux for a period of time to provide a therapeutic effect. Insome embodiments, in order to obtain desired solubility for an activedrug and/or compatibility with peel-forming agents or other ingredientsof the formulation, a mixture of two or more non-volatile solvents canbe used to form the non-volatile solvent system.

The term “solvent vehicle” describes compositions that include both avolatile solvent system and non-volatile solvent system. The volatilesolvent system is chosen so as to evaporate from the adhesive peelableformulation quickly to form a solidified peelable layer, and thenon-volatile solvent system is formulated or chosen to substantiallyremain with the solidified peelable layer after volatile solvent systemevaporation to achieve continued delivery of the drug. Typically, thedrug can be partially or completely dissolved in the solvent vehicle orformulation as a whole. Likewise, the drug can also be partially orcompletely solubilizable in the non-volatile solvent system once thevolatile solvent system is evaporated. Formulations in which the drug isonly partially dissolved in the non-volatile solvent system after theevaporation of the volatile solvent system have the potential tomaintain longer duration of sustained delivery, as the undissolved drugcan dissolve into the non-volatile solvent system as the dissolved drugis being depleted from the solidified peelable layer during drugdelivery.

“Adhesive peelable formulation” or “adhesive peel-forming formulation”refers to a composition that has a viscosity suitable for application toa skin surface prior to evaporation of its volatile solvent(s), andwhich can become a solidified peelable layer (or a peel) afterevaporation of at least a portion of the volatile solvent(s).

The term “drying time” refers to the time it takes for the formulationto form a non-messy solidified surface after application on skin understandard skin and ambient conditions, and with standard testingprocedure. “Standard skin” or “normal skin” is defined as dry, healthyhuman skin with a surface temperature of between 32° C. to 36° C.;standard ambient conditions are defined from 20° C. to 25° C. and from20% to 80% relative humidity. The standard testing procedure is asfollows. To standard skin at standard ambient conditions is applied anapproximately 0.2 mm layer of the adhesive peel-forming formulation andthe drying time is measured. The drying time is defined as the time ittakes for the formulation to form a non-messy surface such that theformulation does not lose mass by adhesion to a piece of 100% cottoncloth pressed onto the formulation surface with a pressure of between 5and 10 g/cm² for 5 seconds.

When a composition is said to have a viscosity “suitable forapplication” to a skin surface, this means the composition has aviscosity that is high enough so that the composition does notsubstantially run off the skin after being applied to skin, but also hasa low enough viscosity so that it can be easily spread onto the skin. Aviscosity range that meets this definition can range from 100 cP to3,000,000 cP (centipoises), and more preferably from 1,000 cP to1,000,000 cP.

“Solidified peelable layer” or “peel” describes the solidified or driedlayer of an adhesive peel-forming formulation after at least a portionof the volatile solvent system has evaporated. The peel remains adheredto the skin, and is preferably capable of maintaining good contact withthe patient's skin for substantially the entire duration of applicationunder normal skin and ambient conditions. The peel also exhibitssufficient tensile strength so that it can be peeled off the skin at theend of the application in one piece or several large pieces (as opposedto a layer with weak tensile strength that breaks into many small piecesor crumbles when removed from the skin).

With these definitions in mind, the present invention is related tonovel formulations that are typically in the initial form of semi-solids(including creams, gels, pastes, ointments, and other viscous liquids),which can be easily applied onto the skin as a layer, and can quickly(from 15 seconds to 4 minutes under normal skin and ambient conditions)to moderately quickly (from 4 to 15 minutes under normal skin andambient conditions) change into a solidified peelable layer or peel,e.g., a coherent and soft solid layer, for drug delivery. A solidifiedpeelable layer or peel thus formed is capable of delivering drug to theskin, into the skin, across the skin, etc., at substantially constantrates, over an sustained period of time, e.g., hours to tens of hours,so that most of the active drug is delivered after the solidifiedpeelable layer is formed. Additionally, the solidified peelable layertypically adheres to the skin, but has a solidified, minimally-adhering,outer surface which is formed relatively soon after application andwhich does not substantially transfer to or otherwise soil clothing orother objects that a subject is wearing or that the peel mayinadvertently contact. The solidified peelable layer can also beformulated such that it is highly flexible and stretchable, and thuscapable of maintaining good contact with a skin surface, even if theskin is stretched during body movement, such as at a knee, finger,elbow, or other joints.

In selecting the various components that can be used, e.g., drug,solvent vehicle of volatile solvent system and non-volatile solventsystem, peel-forming agent(s), etc., various considerations can occur.For example, the volatile solvent system can be selected frompharmaceutically or cosmetically acceptable solvents known in the art.Examples of such volatile solvents include water, ethanol, propylalcohol, ethyl acetate, acetone, or the like. Additionally, thesevolatile solvents should be chosen to be compatible with the rest of theformulation. It is desirable to use an appropriate weight percentage ofthe volatile solvent(s) in the formulation. Too much of the volatilesolvent system prolongs the drying time. Too little of the volatilesolvent system can make it difficult to spread the formulation on theskin. For most formulations, the weight percentage of the volatilesolvent(s) can be from about 2 wt % to about 50 wt %, and morepreferably from about 4 wt % to about 30 wt %.

The non-volatile solvent system can also be chosen or formulated to becompatible with the peel-forming agent, the drug, the volatile solvent,and any other ingredients that may be present. For example, thepeel-forming agent can be chosen so that it is dispersible or soluble inthe non-volatile solvent system. Most non-volatile solvent systems andsolvent vehicles as a whole will be formulated appropriately afterexperimentation. For instance, certain drugs have good solubility inpoly ethylene glycol (PEG) having a molecular weight of 400 (PEG 400,non-volatile solvent) but poor solubility in glycerol (non-volatilesolvent) and water (volatile solvent). However, PEG 400 cannoteffectively dissolve poly vinyl alcohol (PVA), and thus, is not verycompatible alone with PVA, a peel-forming agent. In order to dissolvesufficient amount of an active drug and use PVA as a peel-forming agentat the same time, a non-solvent system including PEG 400 and glycerol(compatible with PVA) in an appropriate ratio can be formulated,achieving a compatibility compromise. As a further example ofcompatibility, non-volatile solvent/film forming agent incompatibilityis observed when Span 20 is formulated into a peel formulationcontaining PVA. With this combination, Span 20 can separate out of theformulation and form an oily layer on the surface of the peel. Thus,appropriate film forming agent/non-volatile solvent selections aredesirable in developing a viable formulation and compatiblecombinations.

Non-volatile solvent(s) that can be used alone or in combination to formnon-volatile solvent systems can be selected from a variety ofpharmaceutically acceptable liquids, including but not limited toglycerol, poly ethylene glycol having a weight average molecular weightfrom about 200 MW to 800 MW, mineral oil, petrolatum, castor oil,essential oils such as eugenol, menthol, cineole, or rose oil, n-methylpyrrolidone, vegetable oils, honey, oleyl alcohol, dipropylene glycol,polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzedC₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides, oleicacid, dimethylsulfoxide (DMSO), fatty alcohol, isopropyl myristate(IPM), triacetin, ethyl oleate, isostearic acid, medium chain fatty acidand other fatty acids, and mixtures thereof. In addition to these andother considerations, the non-volatile solvent system can also serve asplasticizer in the adhesive peelable formulation so that when thesolidified peelable layer is formed, the layer is flexible, stretchable,and/or otherwise “skin friendly.”

Certain volatile and/or nonvolatile solvent(s) that are irritating tothe skin may be desirable to use to achieve the desired solubilityand/or permeability of the drug. It is also desirable to add compoundsthat are both capable of preventing or reducing skin irritation and arecompatible with the formulation. For example, in a formulation where thevolatile solvent is capable of irritating the skin, it would be helpfulto use a non-volatile solvent that is capable of reducing skinirritation. Examples of solvents that are known to be capable ofpreventing or reducing skin irritation include, but are not limited to,glycerin, honey, and propylene glycol.

The selection of the peel-forming agent can also be carried out inconsideration of the other components present in the adhesive peelableformulation. The peel-forming agent can be selected or formulated to becompatible to the drug and the solvent vehicle (including the volatilesolvent(s) and the non-volatile solvent system), as well as providedesired physical properties to the solidified peelable layer once it isformed. Depending on the drug, solvent vehicle, and/or other componentsthat may be present, the peel-forming agent can be selected from avariety of agents, including but not limited to polyvinyl alcohol,polyvinyl pyrrolidone, carrageenin, gelatin, dextrin, gelatin, guar gum,polyethylene oxide, starch, xantham gum, cellulose derivatives includinghydroxyethylcellulose, ehtylcellulose, carboxymethylcellulose,hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycolco-polymers and methyacrylic acid-ethyl acrylate copolymers such asBASF's Kollicoat polymers, methacrylic acid and methacrylate basedpolymers such as poly(methacrylic acid) copolyemers andmethylmethacrylate copolymers, including Rohm & Haas' Eudragit polymers,e.g., Eudragit E, Eudragit R L, Eudragit R S, and polymers of the sameor similar chemical nature but are generic or under different brandnames or chemical names, and mixtures thereof. Many other film formingpolymers may also be suitable as the peel-forming agent, depending onthe solvent vehicle components, the drug, and the specific functionalrequirements of the given formulation.

The non-volatile solvent system and the peel-forming agent should becompatible with each other. Compatibility is defined as i) thepeel-forming agent does not substantially negatively influence thefunction of the non-volatile solvent system; ii) the peel-forming agentcan hold the non-volatile solvent system in the solidified peelablelayer so that substantially no non-volatile solvent oozes out of thelayer, and iii) the solidified peelable layer formed with the selectednon-volatile solvent system and the peel-forming agent has acceptableflexibility, rigidity, tensile strength, elasticity, and adhesiveness.The weight ratio of the non-volatile solvent system to the peel-formingagent can be from about 0.01:1 to about 2:1. In another aspect, theratio between the non-volatile solvent system and the peel-forming agentcan be from about 0.2:1 to about 1.2:1.

To provide some practical parameters, typically, concentrations ofactive drugs in topical formulations rarely exceed 10 wt % (by weight ofactive drug in weight of total formulation). If on embodiment, if thenon-volatile solvent system of a formulation makes up 30 wt % of thetotal formulation weight, this means the concentration of the activedrug in the non-volatile solvent system is about 25 wt %. In such aformulation, the permeation driving force will be significantly reducedif the solubility of the non-volatile solvent system for the drug ismuch higher than 25 wt %. The maximum drug concentrations in manyphysically and commercially viable products are significantly less than10 wt %, which in turn means the upper limits of the window of operablesolubility are significantly lower for those systems, more likely in the1 wt % to 10 wt % range.

The thickness of the formulation layer applied on the skin should alsobe appropriate for a given formulation and desired drug deliveryconsiderations. If the layer is too thin, the amount of the drug may notbe sufficient to support sustained delivery over the desired length oftime. If the layer is too thick, it may take too long to form anon-messy outer surface of the solidified peelable layer. If the drug isvery potent and the peel has very high tensile strength, a layer as thinas 0.01 mm may be sufficient. If the drug has rather low potency and thepeel has low tensile strength, a layer as thick as 2-3 mm maybe needed.Thus, for most drugs and formulations, the appropriate thickness can befrom about 0.01 mm to about 3 mm, but more typically, from about 0.05 mmto about 1 mm.

The flexibility and stretchability of a solidified peelable layer, orpeel, can be desirable in some applications. For instance, certainnon-steroidal anti-inflammatory agents (NSAIDs) can be applied directlyover joints and muscles for transdermal delivery into joints andmuscles. However, skin areas over joints and certain muscle groups areoften significantly stretched during body movements. Such movementprevents non-stretchable patches from maintaining good skin contact.Lotions, ointments, creams, gels, pastes, or the like also may not besuitable for use for the reasons cited above. As such, in transdermaldelivery of NSAIDs into joints and/or muscles, the peel-formingformulations of the present invention can offer unique advantages andbenefits. It should be pointed out that although good stretchability canbe desirable in some applications. The peel-forming formulations of thepresent invention do not always need to be stretchable, as certainapplications of the present invention do not necessarily benefit fromthis property. For instance, if the formulation is applied on a smallfacial area overnight for treating acne, a patient would experienceminimal discomfort and formulation-skin separation even if the peel isnot stretchable, as facial skin usually is not stretched very muchduring a sleep cycle.

A further feature of a formulation is related to the drying time. If aformulation dries too quickly, the user may not have sufficient time tospread the formulation into a thin layer on the skin surface before theformulation is solidified, leading to poor skin contact. If theformulation dries too slowly, the patient may have to wait a long timebefore resuming normal activities (e.g. putting clothing on) that mayremove un-solidified formulation. Thus, it is desirable for the dryingtime to be longer than about 15 seconds but shorter than about 15minutes, and preferably from about 0.5 minutes to about 4 minutes.

Other benefits of the solidified peelable layers of the presentinvention include the presence of a physical barrier that can be formedby the material itself. For instance, local anesthetic agents and otheragents such as clonidine may be delivered topically for treating painrelated to neuropathy, such as diabetic neuropathic pain. Since many ofsuch patients feel tremendous pain, even when their skin area is onlygently touched, the physical barrier of the solidified peelable layercan prevent or minimize pain caused by accidental contact with objectsor others.

These and other advantage can be summarized as follows. The solidifiedpeelable layers of the present invention can be prepared in an initialform that is easy to apply as a semisolid dosage form. Additionally,upon volatile solvent system evaporation, the dosage form is relativelythick and can contain much more active drug than a typical layer oftraditional cream, gel, lotion, ointment, paste, etc., and further, isnot as subject to unintentional removal. After the evaporation of thevolatile solvent(s) and the formation of the solidified peelable layer,the drug in the remaining non-volatile solvent system whose solubilitywith respect to the drug is within the window of operable solubility forthe drug can provide desired delivery rates of the drug over sustainedperiods of time. Further, as the solidified peelable layer remainsadhesive and is peelable, easy removal of the solidified peelable layercan occur, usually without the aid of a solvent or surfactant. In someembodiments, the adhesion to skin and elasticity of the material is suchthat the solidified peelable layer will not separate from the skin uponskin stretching at highly stretchable skin areas, such as over jointsand muscles. For example, in one embodiment, the solidified peelablelayer can be stretched to 10% or greater in one direction withoutcracking, breaking, and/or separating form a skin surface to which thepeelable layer is applied. In another embodiment, the area of thesolidified peelable layer that contacts the skin can be stretched to a10% increase in area without cracking, breaking, and/or separating forma skin surface to which the peelable layer is applied. Still further,the solidified peelable layer can be configured to advantageouslydeliver drug and protect sensitive skin areas without cracking orbreaking.

Specific examples of applications that can benefit from the systems,formulations, and methods of the present invention are as follows. Inone embodiment, a solidified peelable layer including bupivacaine,lidocaine, or ropivacaine, can be formulated for treating diabetic andpost herpetic neuralgia. Alternatively, dibucanine and an alpha-2agonist such as clonidine can be formulated in a peel for treating thesame disease. In another embodiment, retinoic acid and benzoyl peroxidecan be combined in a solidified peelable layer for treating acne, oralternatively, 1 wt % clindamycin and 5 wt % benzoyl peroxide can becombined in a peel for treating acne. In another embodiment, a retinolpeel-forming formulation (OTC) can be prepared for treating wrinkles, ora lidocain peel-forming formulation can be prepared for treating backpain.

Additional applications include delivering drugs for treating certainskin conditions, e.g., psoriasis, skin cancer, etc., particularly thosethat occur over joints or muscles where a transdermal patch may not bepractical. For example, peel-forming formulations containing imiquimodcan be formulated for treating skin cancer, common and genital warts,and actinic keratosis. Peel-forming formulations containing antiviraldrugs such as acyclovir, penciclovir, famciclovir, valacyclovir,steroids, behenyl alcohol can be formulated for treating herpes viralinfections such as cold sores on the face and genital areas.Peel-forming formulations containing non-steroidal anti-inflammatorydrugs (NSAIDs), capsaicin, alpha-2 agonists, and/or nerve growth factorscan be formulated for treating soft tissue injury and muscle-skeletalpains such as joint and back pain of various causes. As discussed above,patches over these skin areas typically do not have good contact oversustained period of time, especially for a physically active patient,and may cause discomfort. Likewise, traditional semi-solid formulationssuch as creams, lotions, ointments, etc., may prematurely stop thedelivery of a drug due to the evaporation of solvent and/orunintentional removal of the formulation. The solidified adhesiveformulations of the present invention address the shortcomings of bothof these types of delivery systems.

One embodiment entails a peel containing a drug from the class ofalpha-2 antagonists which is applied topically to treat neuropathicpain. The alpha-2 agonist is gradually released from the formulation toprovide pain relief over a sustained period of time. The formulation canbecome a coherent, soft solid after 2-4 minutes and remains adhered tothe body surface for the length of its application. It is easily removedafter drying without leaving residual formulation on the skin surface.

Another embodiment involves a peel formulation containing capsaicinwhich is applied topically to treat neuropathic pain. The capsaicin isgradually released from the formulation for treating this pain over asustained period of time. The formulation can become a coherent, softsolid after 2-4 minutes and remains adhered to the body surface for thelength of its-application. It is easily removed any time after dryingwithout leaving residual formulation on the skin surface.

Still another embodiment involves a peel formulation containing a drugselected from the NSAID class, such as piroxicam, diclofenac,indomethacin, which is applied topically to treat symptoms of back pain,muscle tension, or myofascial pain or a combination thereof. The NSAIDis gradually released from the formulation to provide pain relief over asustained period of time. The formulation can become a coherent, softsolid after 2-4 minutes and remains adhered to the body surface for thelength of its application. It is easily removed any time after dryingwithout leaving residual formulation on the skin surface.

A further embodiment involves a peel formulation containing at least onealpha-2 agonist drug and at least one local anesthetic drug which isapplied topically to treat neuropathic pain. The drugs are graduallyreleased from the formulation to provide pain relief over a sustainedperiod of time. The formulation can become a coherent, soft solid after2-4 minutes and remains adhered to the body surface for the length ofits application. It is easily removed any time after drying withoutleaving residual formulation on the skin surface.

A similar embodiment can include a peel formulation containing drugscapsaicin and a local anesthetic drug which is applied topically to theskin to provide pain relief. Another embodiment can include a peelformulation containing the combination of a local anesthetic and aNSAID. In both of the above embodiments the drugs are gradually releasedfrom the formulation to provide pain relief over an sustained period oftime. The formulation can become a coherent, soft solid after 2-4minutes and remains adhered to the body surface for the length of itsapplication. It is easily removed any time after drying without leavingresidual formulation on the skin surface.

In another embodiment, peel-forming formulations for the delivery ofdrugs that treat the causes or symptoms of diseases involving joints andmuscles can also benefit from the systems, formulations, and methods ofthe present invention. Such diseases that may be applicable include, butnot limited to, osteoarthritis (OA), rheumatoid arthritis (RA), jointand skeletal pain of various other causes, myofascial pain, muscularpain, and sports injuries. Drugs or drug classes that can be used forsuch applications include, but are not limited to, non-steroidalanti-inflammatory drugs (NSAIDs) such as ketoprofen and diclofanec,COX-2 selective NSAIDs and agents, COX-3 selective NSAIDs and agents,local anesthetics such as lidocaine, bupivacaine, ropivacaine, andtetracaine, steroids such as dexamethasone.

Delivering drugs for the treatment of acne and other skin conditions canalso benefit from principles of the present invention, especially whendelivering drugs having low skin permeability. Currently, topicalretinoids, peroxides, and antibiotics for treating acne are mostlyapplied as traditional semisolid gels or creams. However, due to theshortcomings as described above, sustained delivery over many hours isunlikely. For example, clindamycin, benzoyl peroxide, and erythromycinmay be efficacious only if sufficient quantities are delivered into hairfollicles. However, a semisolid formulation, such as the popular acnemedicine benzaclin gel, typically loses most of its solvent (water inthe case of benzaclin) within a few minutes after the application, whichlikely substantially compromises the sustained delivery of the drug. Theformulations of the present invention typically do not have thislimitation.

In another embodiment, the delivery of drugs for treating neuropathicpain can also benefit from the methods, systems, and formulations of thepresent invention. A patch containing a local anesthetic agent, such asLidoderm™, is widely used for treating neuropathic pain, such as paincaused by post-herpetic neuralgia and diabetes induced neuropathic pain.Due to the limitations of the patch as discussed above, the solidifiedpeelable layers prepared in accordance with the present inventionprovide some unique benefits, as well as provide a potentially lessexpensive alternative to the use of a patch. Possible drugs deliveredfor such applications include, but are not limited to, local anestheticssuch as lidocaine, prilocaine, tetracaine, bupivicaine, etidocaine; andother drugs including capsaicin and alpha-2 agonists such as clonidine.

In yet another embodiment, the delivery of medication for treating wartsand other skin conditions would also benefit from long periods ofsustained drug delivery. Such drugs that can be used in the formulationsof the present invention include, but are not limited to, salicylic acidand imiquimod.

In another embodiment, the delivery of natural substances and nutrientssuch as retinol (Vitamin A) and humectants or emollients to the skin forcosmetic purposes can also benefit from the systems, formulations, andmethods of the present invention.

A further embodiment involves the delivery of anti-fungal agents such asciclopirox, imidazoles, miconazole, clotrimazole, econazole,ketoconazole, oxiconazole, sulconazole and allylamine derivatives suchas butenafine, naftifine, and terbinafine, to the skin so as toeliminate or alleviate various fungal disorders. Delivery can beaccomplished through the systems, formulations and methods of thepresent invention.

In another embodiment, delivery of antiviral agents such as acyclovir,trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir,gancyclovir, valacyclovir, podofilox, podophyllotoxin,ribavirin,abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine,stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir,ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin,rimantadine, zanamivir, and combinations thereof. Antiviral treatmentcould be used to treat both localized and systemic viral infections.

A further embodiment involves the peel-forming formulations for thedelivery of topically and systemically targeted anti-infectants such asantibiotics.

Other drugs that can be used include humectants, emollients, and otherskin care compounds.

The window of operable solubility for certain drugs and drug classes areprovided below for exemplary purposes, though it should be noted thatthe specific non-volatile solvent system can affect these ranges to somedegree. For example, a local anesthetic agent can have a window ofoperable solubility is from about 50 μg/g to about 400 mg/g, andpreferably from 100 μg/g to 200 mg/g. An antiviral agent can have awindow of operable solubility from about 50 μg/g to about 400 mg/g, andpreferably from 100 μg/g to 200 mg/g. A non-steroidal anti-inflammatoryagent can have a window of operable solubility from about 200 μg/g toabout 400 mg/g, and preferably from 1 mg/g to 200 mg/g. Imiquimod canhave a window of operable solubility from about 100 μg/g to about 400mg/g, and preferably from 1 mg/g to 200 mg/g. Testosterone can have awindow of operable solubility from about 0.5 mg/g to about 400 mg/g, andpreferably from 1 mg/g to 200 mg/g. An alpha-2 agonist can have a windowof operable solubility from about 10 μg/g to about 400 mg/g, andpreferably from 1 mg/g to 200 mg/g. An antibiotic can have a window ofoperable solubility from about 10 μg/g to about 400 mg/g, and preferably1 mg/g to 200 mg/g. Capsaicin can have a window of operable solubilityfrom about 10 μg/g to about 400 mg/g, and preferably from 100 μg/g to200 mg/g. A retenoid can have a window of operable solubility from about5 μg/g to about 400 mg/g, and preferably from 100 μg/g to 200 mg/g.

EXAMPLES

The following examples illustrate the embodiments of the invention thatare presently best known. However, it is to be understood that thefollowing are only exemplary or illustrative of the application of theprinciples of the present invention. Numerous modifications andalternative compositions, methods, and systems may be devised by thoseskilled in the art without departing from the spirit and scope of thepresent invention. The appended claims are intended to cover suchmodifications and arrangements. Thus, while the present invention hasbeen described above with particularity, the following examples providefurther detail in connection with what are presently deemed to be themost practical and preferred embodiments of the invention.

Example 1 Skin Permeation Methodology

Hairless mouse skin (HMS) was used as the model membrane for the invitro flux studies described in herein. Freshly separated epidermisremoved from the abdomen of a hairless mouse was mounted carefullybetween the donor and receiver chambers of a Franz diffusion cell. Thereceiver chamber was filled with pH 7.4 phosphate buffered saline (PBS).The experiment was initiated by placing test formulations (of Examples2-5) on the stratum corneum (SC) of the skin sample. Franz cells wereplaced in a heating block maintained at 37° C. and the HMS temperaturewas maintained at 35° C. At predetermined time intervals, 800 μLaliquots were withdrawn and replaced with fresh PBS solution. Skin flux(μg/cm²/h) was determined from the steady-state slope of a plot of thecumulative amount of permeation versus time. It is to be noted thathuman cadaver skin was used as the model membrane for the in vitro fluxstudies described in Example 10. The mounting of the skin and thesampling techniques used were the same as described previously for theHMS studies.

Examples 2-5 Adhesive Peel-forming Formulations Including Ketoprofen andin Vitro Testing

A stretchable adhesive peelable formulation for transdermal delivery ofketoprofen (which is suitable for delivery via skin on joints andmuscles) was prepared which includes saturated amount of ketoprofenin-an excipient mixture (more ketoprofen than that can be dissolved inthe excipient mixture) to form an adhesive peelable formulation, some ofwhich are prepared in accordance with embodiments of the presentinvention. The excipient mixture, which was a viscous and transparentfluid, was prepared using the ingredients as shown in Table 1. TABLE 1Ketoprofen Peel-forming Formulation Components. Examples Ingredients* 23 4 5 PVA (polyvinyl alcohol) 1 2 2 2 PEG-400 (polyethylene glycol) 1 10.27 1.75 PVP-K90 (polyvinyl pyrrolidone) 1 0 0 0 Glycerol 1 1 1.8 0.27Water 2.6 5.3 5.4 5.4 Ethanol 3 0 0 0 Ketoprofen*Ingredients are noted as parts by weight.

Each of the compositions of Examples 2-5 were studied for flux ofketoprofen, as shown in Table 2, as follows: TABLE 2 Steady-state fluxof ketoprofen through hairless mouse skin from various adhesive peelableformulations at 35° C. Average flux Formulation mcg/cm²/h* Example 2 8 ±3 Example 3 21 ± 6  Example 4 3 ± 1 Example 5   1 ± 0.4*The flux values represent the mean and SD of three determinations.The quantity of ketoprofen that permeated across the hairless mouse skinstratum corneum overtime is shown in FIG. 1.

Regarding formulation described in Example 2, ethanol and water formedthe volatile solvent system, while a 1:1 mixture of glycerol and PEG 400formed the non-volatile solvent system. Through experimentation, it wasdetermined that PEG 400 is a better solvent than glycerol forketoprofen, while glycerol is much more compatible with PVA than PEG400. The non-volatile solvent system of glycerol and PEG 400, thus, wereused together to provide appropriate solubility for the drug, whilebeing reasonably compatible with PVA. In the formulation in Example 2,PVA and PVP act as the peel-forming agents. Further, in this embodiment,glycerol and PEG 400 also serve as plasticizers in the adhesive peelableformulation formed after the evaporation of the volatile solvents.Without the presence of glycerol and PEG 400, a film formed by PVA andPVP alone would have been rigid and non-stretchable. As can be seen fromFIG. 1, the linear relationship between the cumulative amount versustime indicates that ketoprofen was delivered at relatively constant rateover 8 hours after evaporation of at least a portion of the volatilesolvents.

Regarding the formulation of Example 3, the adhesive peelable formationformed had similar physical properties as that of Formulation 1, thoughthe transdermal flux across hairless mouse skin was higher. Thissuggests that the peel-forming agent, 1:1 PVA:PVP-K-90 in Example 2 andpure PVA in example 3, have an impact on permeation.

The formulation in Example 4 delivered less ketoprofen than theformulations of Examples 2 or 3. One reason for the difference could bedue to the low concentration of PEG 400 (a good solvent for ketoprofen)in the non-volatile solvent system, which may have resulted in lowerquantities of dissolved ketoprofen, and thus, lower skin flux. If atherapeutically effective amount of drug is not supported by this lowskin flux, then this example illustrates a scenario in which thesolubility is lower than the “window of operable solubility.”

The formulation of Example 5 delivered much less ketoprofen than theformulations in Examples 2 and 3. One possible reason for the reducedflux is believed to be the reduced permeation driving force caused bythe high concentration of PEG 400 in the non-volatile solvent system,which resulted in too high of solubility for ketoprofen, Thisillustrates a scenario in which the solubility is higher than the“window of operable solubility.” Thus, too low of solubility is not theonly consideration when trying to achieve skin flux. In thiscircumstance, the drug was too “comfortable” or too soluble in thenon-volatile solvent system to provide effective skin flux. Thus, highsolubility of the ketoprofen put the drug outside of a window ofoperable solubility to be effective.

The only significant difference among the formulations in Examples 3, 4,and 5, respectively is with respect to the non-volatile solvent system,or more specifically, the PEG 400:glycerol weight ratio. These resultsreflect the impact of the non-volatile solvent system on skin flux andsupport for the aforementioned principle that the non-volatile solventsystem provides solubility of the drug within the window of operablesolubility for delivering therapeutically effective amounts of the drugto, into, or through the skin.

Example 6 Adhesive Peelable Formulation Including Lidocaine and in VitroTesting

A stretchable adhesive peelable formulation for transdermal delivery oflidocaine was prepared which includes saturated amount of lidocaine inan excipient mixture to form an adhesive peelable formulation inaccordance with embodiments of the present invention. The peelformulation was prepared from the ingredients as shown in Table 3. TABLE3 Lidocaine Peel-forming Formulation Components. Example Ingredients* 6PVA 1 Eudgragit E-100** 1 PVP-K90 0.5 Glycerol 0.75 PEG-400 0.75 Water 2Ethanol 2 Lidocaine*Ingredients are noted as parts by weight.**from Rohm & Haas.

TABLE 4 Steady-state Flux of Lidocaine through Hairless Mouse Skin fromVarious Adhesive Peel-forming Formulations at 35° C. Average fluxFormulation mcg/cm²/h* Example 6 47 ± 3The quantity of lidocaine that permeated across the hairless mouse skinstratum corneum over time is shown in FIG. 2.

The adhesive peelable formulation of lidocaine formulation in thepresent example had similar physical properties to the formulations inExamples 2-5. The transdermal flux across hairless mouse skin wasacceptable and steady-state delivery was maintained over 8 hours.

Example 7 Ropivacaine Flux Using Non-Volatile Solvents

Ropivacaine base flux across hairless mouse skin was determined inseveral saturated non-volatile solvents as described in Example 1. TABLE5 Steady-state Flux Values of Ropivacaine through Hairless Mouse Skinfrom Saturated Non-volatile Solvent Systems at 35° C. Average fluxNon-Volatile Solvent mcg/cm²/h* ISA (isostearic acid) 11 ± 2  Glycerin1.2 ± 0.7 Tween 20 2.4 ± 0.1 Mineral Oil 8.9 ± 0.6 Span 20 26 ± 8 *The flux values represent the mean and SD of three determinationsIt is estimated that for treating skin neuropathic pain, the flux needsto be above 10 μg/cm²/h. The range in ropivacaine flux values fromvarious non-volatile solvents illustrates that some solvents havesolubilities that are within the window of operable solubility.

Examples 8-9 Adhesive Peelable Formulations with Ropivacaine

A stretchable adhesive peelable formulation for transdermal delivery ofropivacaine was prepared which includes a specified amount ofropivacaine in an excipient mixture to form an adhesive peelableformulation in accordance with embodiments of the present invention. Thepeel formulations contained the following components: TABLE 6Ropivacaine Peelable Formulation Ingredients. Examples Ingredients* 8 9Eudragit RL-100 1 1 Ethanol 0.6 0.6 ISA (isostearic acid) 0.34 0.34 PG(propylene glycol) 0.2 0.1 Trolamine 0.1 0.1 Glycerol 0.2 0.3Ropivacaine 0.085 0.085* Ingredients are noted as parts by weight.

These formulations were applied to HMS skin as described in Example 1,and the ropivacaine flux was measured. A summary of the results from invitro flux studies carried out with the formulations in Examples 8 and 9is listed in Table 7. TABLE 7 Steady-state Flux of Ropivacaine throughHairless Mouse Skin from Various Adhesive Peelable Formulations at 35°C. Average flux Formulation mcg/cm²/h* Example 8 36 ± 5 Example 9 32 ± 2*The flux values represent the mean and SD of three determinationsThe quantity of ropivacaine that permeated across the hairless mouseskin as a function of time is shown in FIG. 3. Regarding the formulationdescribed in Examples 8 and 9, ethanol was used as the volatile solvent,and the ISA, glycerol, and PG mixture was used as the non-volatilesolvent system. Through experimentation, it was determined that ISA andpropylene glycol used together to provide the appropriate solubility forthe drug, while being compatible with the Eudragit RL-100 film former.Further, in this embodiment, glycerol serves as a plasticizer in thepeelable formulation after the ethanol (volatile solvent) hasevaporated. The presence of trolamine as a pH adjuster providessolubility of the drug within the window of operable solubility fordelivering therapeutically effective amounts of the drug into the skin.The linearity of the cumulative amount versus time curve indicates thatropivacaine was delivered at a relatively constant rate for 8 hours..

Example 10 Adhesive Peel-Forming Formulation Including Diclofenac

A stretchable adhesive peelable formulation for transdermal delivery ofdiclofenac was prepared which includes saturated amount of diclofenac inan excipient mixture to form an adhesive peelable formulation inaccordance with embodiments of the present invention. The peel-formingformulation contained the following components: TABLE 8 DiclofenacPeelable Formulation Ingredients. Example Ingredients* 10 PVA 1 Water1.5 Eudragit E-100 1 Ethanol 1 Span 20 0.6*Ingredients are noted as parts by weight.This formulation was applied to a human cadaver skin sample, and theflux across the skin was measured using the method using the methoddescribed in Example 1, and was found to be 5±2 μg/cm²/h. The quantityof diclofenac that permeated across the human epidermal membrane overtime is shown in FIG. 4. The adhesive peelable formulation of thediclofenac formulation had similar physical properties to theformulations in Example 2-6, and 8 and 9. The transdermal flux acrosshuman skin for 30 hours was acceptable.

Example 11 Adhesive Peelable Formulation Flexibility

A formulation similar to the formulation in Example 2 composition (withno ketoprofen) was applied onto a human skin surface at an elbow jointand a finger joint, resulting in a thin, transparent, flexible, andstretchable film. After a few minutes of evaporation of the volatilesolvents (ethanol and water), a solidified peelable layer that waspeelable was formed. The stretchable film had good adhesion to the skinand did not separate from the skin on joints when bent, and could easilybe peeled away from the skin.

Example 12 Non-Volatile Solvent System and Peel-Forming AgentCompatibility

The effect of solubility on permeation, compatibility between thenon-volatile solvent system and the peel-forming agent is shown in thisexample. Ropivacaine base solubility in isostearic acid (ISA) wasexperimentally determined to be slightly above 1:4, meaning 1 gramropivacaine base can completely dissolve in 4 gram isostearic acid. Inone experiment, two solutions were made: Solution A included 1 partropivacaine base and 4 parts isostearic acid. Solution B included 1 partropivacaine base, 4 parts isostearic acid, and 1 part trolamine. (allparts are in weight). All ropivacaine in Solution A was dissolved, butonly a portion of ropivacaine in solution B was dissolved. Thetransdermal flux across hairless mouse skin generated by the solutionswas measured by a typical Franz Cell system, with the following results:TABLE 9 Flux Across Hairless Mouse Skin, in vitro, in μg/hr/cm² Cell 1Cell 2 Cell 3 Average Solution A 13.1 9.9 9.1 10.7 Solution B 43.2 35.050.0 42.7As can be seen, the flux generated by Solution B is about 4 times thatof Solution A. These results demonstrate that reduction of ropivacainesolubility in isostearic acid (the non-volatile solvent system) by theaddition of trolamine significantly increased the transdermal flux.However, the attempt to incorporate this system into a poly vinylalcohol (PVA) based peel formulation failed because the PVA in theformulation acted as a strong pH buffer that inhibited the effect oftrolamine. Addition of more trolamine, in attempt to over-power the pHbuffer capacity of PVA, caused the loss of the desired peel-formingproperty of PVA. When PVA was replaced by another peel-forming agent,Eudragit RL 100 (Rohm & Haas), the effect of trolamine was not inhibitedand formulations capable of generating fluxes around 30 μg/hr/cm² wereobtained. This demonstrates the benefits of compatibility between thenon-volatile solvent system and the peel-forming agent.

Example 13 Adhesive Peelable Formulation with Ropivacaine

A stretchable adhesive peelable formulation for transdermal delivery ofropivacaine (which is suitable for delivery via skin on joints andmuscles) was prepared from the following ingredients: TABLE 10Ropivacaine Peel-forming Formulation Components Example Ingredients* 13Ropivacaine HCl 0.096 Eudragit RL-100 1.0 Ethanol 0.7 Isostearic Acid0.34 Glycerol 0.3 Propylene Glycol 0.1 Trolamine 0.15*Ingredients are noted as parts by weight.

The ingredients listed above were combined according to the followingprocedure. The Eudragit RL-100 and ethanol were combined in a glass jarand heated to about 60° C. until the Eudragit RL-100 was completelydissolved. Once the Eudragit solution cooled to room temperature, theappropriate amount of ropivacaine HCl was added and mixed thoroughly for1 minute. To this solution, isosteric acid (ISA) was added and themixture was stirred vigorously for 2-3 minutes. One hour later, thesolutions was vigorously mixed again for 2-3 minutes. To this solution,glycerol, propylene glycol, and trolamine were added in sequentialorder. After addition of each ingredient the solution was stirred for 1minute.

Example 14 Ropivacaine Flux

The formulation prepared in accordance with Example 13 was applied toHMS as described in Example 1, and the ropivacaine flux was measured. Asummary of the results is listed in Table 11, as follows: TABLE 11Steady-state Flux of Ropivacaine through Hairless Mouse Skin fromVarious Adhesive Peelable Formulations at 35° C. Average fluxFormulation mcg/cm²/h* Example 13 43 ± 4*The flux values represent the mean and SD of three determinationsThe ropivacaine peel formulations prepared in accordance with Example 13possessed acceptable application properties, e.g., ease of removal ofpeel from the sample tube, ease of spreading on intended skinapplication site, etc., and formed a solidified film in 2-3 minutes. Thesolidified peelable layer becomes more easily peelable in 2 hours, andthe peel remains affixed to the skin surface without any unintendedremoval of the peel for at least 12 hours. At the end of intended use,the peel is easily removed in one continuous piece.

While the invention has been described with reference to certainpreferred embodiments, those skilled in the art will appreciate thatvarious modifications, changes, omissions, and substitutions can be madewithout departing from the spirit of the invention. It is thereforeintended that the invention be limited only by the scope of the appendedclaims.

1. An adhesive peel-forming formulation for dermal delivery of a drug,comprising: a) a drug; b) a solvent vehicle, comprising: i) a volatilesolvent system including one or more volatile solvent, and ii) anon-volatile solvent system including one or more non-volatile solvent,wherein the non-volatile solvent system has a solubility with respect tothe drug that is within a window of operable solubility such that thedrug is deliverable at therapeutically effective rates over a sustainedperiod of time; and c) a peel-forming agent, wherein the formulation hasa viscosity suitable for application and adhesion to a skin surfaceprior to evaporation of the volatile solvent system, and wherein theformulation applied to the skin surface forms a solidified peelablelayer after at least partial evaporation of the volatile solvent system,wherein the drug continues to be delivered after the volatile solventsystem is substantially evaporated.
 2. A formulation as in claim 1,wherein the non-volatile solvent system acts as a plasticizer for saidpeel-forming agent.
 3. A formulation as in claim 1, wherein saidvolatile solvent system comprises water.
 4. A formulation as in claim 1,wherein said volatile solvent system comprises at least one solvent morevolatile than water, and is selected from the group consisting ofethanol, isopropyl alcohol, ethyl acetate, acetone, mixtures thereof,and mixtures with water thereof.
 5. A formulation as in claim 1, whereinthe non-volatile solvent system includes multiple non-volatile solventsadmixed together which provide a solubility for the drug that is withinthe window of operable solubility.
 6. A formulation as in claim 1,wherein the non-volatile solvent system comprises one or more solventsselected from the group consisting of glycerol, polyethylene glycolhaving a weight average molecular weight from about 200 MW to 800 MW,mineral oil, petrolatum, castor oil, n-methyl pyrrolidone, vegetableoil, honey, oleyl alcohol, dipropylene glycol, polyoxyethylenederivative of sorbitan esters, saturated polyglycolyzed C₈ to C₁₀glycerides, polyoxyethylated fatty acid glycerides, dimethylsulfoxide,fatty alcohol, isopropyl myristate, ethyl oleate, essential oilsincluding eugenol and rose oil, oleic acid, oleyl alcohol, isostearicacid, fatty acids including medium chain fatty acids, and mixturesthereof.
 7. A formulation as in claim 1, wherein the peel-forming agentis selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, carrageenin, gelatin, and mixtures thereof.
 8. Aformulation as in claim 1, wherein the peel-forming agent includes amember selected from the group consisting of dextrin, guar gum, xanthamgum, polyethylene oxide having a weight average molecular weight greaterthan about 5,000 Mw, starch, cellulose derivatives, and mixturesthereof.
 9. A formulation as in claim 8, wherein the peel-forming agentincludes a cellulose derivative selected from the group consisting ofhydroxyethylcellulose, ehtylcellulose, carboxymethylcellulose,hydroxypropylcellulose, copolymers of methyl vinyl ether and maleicanhydride, and mixtures thereof.
 10. A formulation as in claim 1,wherein the peel-forming agent is selected from the group consisting ofpolyvinyl alcohol-polyethylene glycol co-polymers, methacrylic acid andmethacrylate-based copolymers including poly(methacrylic acid)copolymers, methylmethacrylate copolymers, methyacrylic acid-ethylacrylate copolymers, and mixtures thereof.
 11. A formulation as in claim1, wherein the drug includes multiple pharmaceutically active agents.12. A formulation as in claim 1, wherein the peel-forming agent includesa methyacrylic polymer.
 13. A formulation as in claim 1, wherein thepeel-forming agent includes a methyacrylic acid-ethyl acrylatecopolymer.
 14. A formulation as in claim 1, wherein the peel-formingagent includes a polyvinyl alcohol-polyethylene glycol copolymer.
 15. Aformulation as in claim 1, wherein the drug is selected from the groupconsisting of non-steroidal anti-inflammatory drugs (NSAIDs) includingketoprofen and diclofanec; COX-2 selective NSAIDs and agents; COX-3selective NSAIDs and agents; local anesthetics including lidocaine,bupivacaine, ropivacaine, and tetracaine; steroids includingdexamethasone; antibiotics, retinoids, clonidine, peroxides, retinol,salicylic acid, imiquimod, humectants, emollients, antiviral drugsincluding acyclovir, penciclovir, famciclovir, valacyclovir steroids,and behenyl alcohol; and combinations thereof.
 16. A formulation as inclaim 1, wherein the drug is ketoprofen.
 17. A formulation as in claim1, wherein the drug is a humectant or emollient.
 18. A formulation as inclaim 1, wherein the drug is a steroid for treating herpes infection.19. A formulation as in claim 1, wherein the drug is a drug for treatinga cold sore.
 20. A formulation as in claim 1, wherein the drug is a drugfor treating genital warts.
 21. A formulation as in claim 1, wherein thedrug is a drug for treating muscle skeletal pain.
 22. A formulation asin claim 1, wherein the drug is diclofenac.
 23. A formulation as inclaim 1, wherein the drug is an antifungal drug.
 24. A formulation as inclaim 23, wherein the antifungal drug is selected from the group ofciclopirox, imidazoles, miconazole, clotrimazole, econazole,ketoconazole, oxiconazole, sulconazole and allylamine derivativesincluding butenafine, naftifine, and terbinafine, and combinationsthereof.
 25. A formulation as in claim 1, wherein the drug is anantiviral drug.
 26. A formulation as in claim 25, wherein the antiviraldrug is selected from the group of acyclovir, trifluridine, idoxuridine,penciclovir, famciclovir, cidofovir, gancyclovir, valacyclovir,acyclovir, podofilox, podophyllotoxin,ribavirin, abacavir, delavirdine,didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine,zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir,amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir,and combinations thereof.
 27. A formulation as in claim 1, wherein thedrug is an anti-infective.
 28. A formulation as in claim 1, wherein thesolidified peelable layer is sufficiently flexible and adhesive to theskin such that when applied to the skin at a human joint, the solidifiedpeelable layer will remain substantially intact on the skin upon bendingof the joint.
 29. A formulation as in claim 1, wherein the peelableformulation is configured to deliver the drug at a substantiallyconstant rate for at least 2 hours following the formation of saidsolidified peelable layer.
 30. A formulation as in claim 1, wherein thepeelable formulation is configured to deliver the drug at asubstantially constant rate for at least 4 hours following the formationof said solidified peelable layer.
 31. A formulation as in claim 1,wherein the peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 8 hours following the formationof said solidified peelable layer.
 32. A formulation as in claim 1,wherein the peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 12 hours following theformation of said solidified peelable layer.
 33. A formulation as inclaim 1, wherein the peel-forming agent is dispersed or solvated in thesolvent vehicle.
 34. A formulation as in claim 1, wherein the window ofoperable solubility is predetermined.
 35. A formulation as in claim 1,wherein the weight ratio of the non-volatile solvent system to thepeel-forming agent is from about 0.01:1 to about 2:1.
 36. A formulationas in claim 1, wherein the weight ratio of the non-volatile solventsystem to the peel-forming agent is from about 0.2:1 to about 1.2:1. 37.A formulation as in claim 1, wherein the volatile solvent system iscapable of causing human skin irritation and at least one non-volatilesolvent of said non-volatile solvent system is capable of reducing theskin irritation.
 38. A formulation as in claim 37, wherein thenon-volatile solvent capable of reducing skin irritation is selectedfrom the group consisting of glycerin, propylene glycol, and honey. 39.A formulation as in claim 1, wherein the solidified peelable layer isformed within 15 minutes of application to the skin surface understandard skin and ambient conditions.
 40. A formulation as in claim 1,wherein the solidified peelable layer is formed within 4 minutes of theapplication to the skin surface under standard skin and ambientconditions.
 41. A formulation as in claim 1, wherein the formulation hasan initial viscosity prior to skin application from about 100 to about3,000,000 centipoises.
 42. A formulation as in claim 1, wherein theformulation has an initial viscosity prior to skin application fromabout 1,000 to about 1,000,000 centipoises.
 43. A formulation as inclaim 1, wherein the weight percentage of the volatile solvent system isfrom about 2 wt % to about 50 wt %.
 44. A formulation as in claim 1,wherein the weight percentage of the volatile solvent system is fromabout 4 wt % to about 30 wt %.
 45. A formulation as in claim 1, whereinthe non-volatile solvent system includes multiple non-volatile solvents,and at least one of the non-volatile solvents improves the compatibilityof the non-volatile solvent system with the peel-forming agent.
 46. Aformulation as in claim 1, wherein the drug is a local anesthetic agentand the window of operable solubility is from about 50 μg/g to about 400mg/g.
 47. A formulation as in claim 1, wherein the drug is an antiviralagent and the window of operable solubility is from about 50 μg/g toabout 400 mg/g.
 48. A formulation as in claim 1, wherein the drug is anon-steroidal anti-inflammatory agent and the window of operablesolubility is from about 200 μg/g to about 400 mg/g.
 49. A formulationas in claim 1, wherein the drug is imiquimod and the window of operablesolubility is from about 100 μg/g to about 400 mg/g.
 50. A formulationas in claim 1, wherein the drug is testosterone and the window ofoperable solubility is from about 0.5 mg/g to about 400 mg/g.
 51. Aformulation as in claim 1, wherein the drug is an alpha-2 agonist andthe window of operable solubility is from about 10 μg/g to about 400mg/g.
 52. A formulation as in claim 1, wherein the drug is an antibioticand the window of operable solubility is from about 10 μg/g to about 400mg/g.
 53. A formulation as in claim 1, wherein the drug is capsaicin andthe window of operable solubility is from about 10 μg/g to about 400mg/g.
 54. A formulation as in claim 1, wherein the drug is a retenoidand the window of operable solubility is from about 5 μg/g to about 400mg/g.
 55. A formulation as in claim 1, wherein the non-volatile solventincludes at least two non-volatile solvents, and wherein one of said atleast two non-volatile solvents is included to improve compatibilitywith the peel-forming agent.
 56. A method of dermally delivering a drug,comprising: a) applying an adhesive peel-forming formulation to a skinsurface of a subject, said adhesive peel-forming formulation,comprising: i) a drug; ii) a solvent vehicle, comprising: a volatilesolvent system including one or more volatile solvent, and anon-volatile solvent system having one or more non-volatile solvent,wherein the non-volatile solvent system has a solubility with respect tothe drug that is within a window of operable solubility such that thedrug can be delivered at therapeutically effective rates over asustained period of time; and iii) a peel-forming agent, wherein theformulation has a viscosity suitable for application and adhesion to askin surface prior to evaporation of the volatile solvent system, andwherein the formulation applied to the skin surface forms a solidifiedpeelable layer after at least partial evaporation of the volatilesolvent system, wherein the drug continues to be delivered after thevolatile solvent system is substantially evaporated; and b) dermallydelivering the drug from the solidified peelable layer to the subject attherapeutically effective rates over a sustained period of time.
 57. Amethod as in claim 56, wherein the step of applying includes applyingthe adhesive peel-forming formulation at a thickness from about 0.01 mmto about 2 mm.
 58. A method as in claim 57, wherein the thickness isfrom about 0.05 mm to about 1 mm.
 59. A method as in claim 56, whereinthe non-volatile solvent system includes multiple non-volatile solventsadmixed together to form a mixture, said mixture providing a solubilityfor the drug that is within the window of operable solubility.
 60. Amethod as in claim 56, wherein the non-volatile solvent system comprisesone or more solvent selected from the group consisting of glycerol,polyethylene glycol having a weight average molecular weight from about200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methylpyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol,polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzedC₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides,dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate,essential oils including eugenol and rose oil, oleic acid, isostearicacid, fatty acids and medium chain fatty acids, and mixtures thereof.61. A method as in claim 56, wherein the peel-forming agent is selectedfrom the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone,carrageenin, gelatin, and mixtures thereof.
 62. A method as in claim 56,wherein the peel-forming agent includes a member selected from the groupconsisting of dextrin, guar gum, xantham gum, polyethylene oxide havinga weight average molecular weight greater than about 5,000 Mw, starch,cellulose derivatives, and mixtures thereof.
 63. A method as in claim62, wherein the peel-forming agent includes a cellulose derivativeselected from the group consisting of hydroxyethylcellulose,ehtylcellulose, carboxymethylcellulose, hydroxypropylcellulose,copolymers of methyl vinyl ether and maleic anhydride, and mixturesthereof.
 64. A formulation as in claim 56, wherein the peel-formingagent is selected from the group consisting of polyvinylalcohol-polyethylene glycol co-polymers, methacrylic acid andmethacrylate-based copolymers including poly(methacrylic acid)copolymers, methylmethacrylate copolymers, methyacrylic acid-ethylacrylate copolymers, and mixtures thereof.
 65. A method as in claim 56,wherein the drug includes multiple pharmaceutically active agents.
 66. Amethod as in claim 56, wherein the drug is selected from the groupconsisting of non-steroidal anti-inflammatory drugs (NSAIDs) includingketoprofen and diclofanec; COX-2 selective NSAIDs and agents; COX-3selective NSAIDs and agents; local anesthetics including lidocaine,bupivacaine, ropivacaine, and tetracaine; steroids includingdexamethasone; antibiotics, retinoids, clonidine, peroxides, retinol,salicylic acid, imiquimod, humectants, emollients, antiviral drugsincluding acyclovir, penciclovir, famciclovir, valacyclovir steroids,and behenyl alcohol; and mixtures thereof.
 67. A method as in claim 56,wherein the drug is a steroid for treating herpes infection.
 68. Amethod as in claim 56, wherein the drug is for treating a cold sore. 69.A formulation as in claim 56, wherein the drug is a drug for treatinggenital warts.
 70. A method as in claim 56, wherein the drug is fortreating muscle skeletal pain.
 71. A formulation as in claim 56, whereinthe drug is an antifungal drug selected from the group consisting ofciclopirox, imidazoles, miconazole, clotrimazole, econazole,ketoconazole, oxiconazole, sulconazole and allylamine derivativesincluding butenafine, naftifine, terbinafine, and combinations thereof.72. A formulation as in claim 56, wherein the drug is an antiviral drugselected from the group consisting of acyclovir, trifluridine,idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir,valacyclovir, acyclovir, podofilox, podophyllotoxin,ribavirin, abacavir,delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine,zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir,saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine,zanamivir, and combinations thereof.
 73. A method as in claim 56,wherein the solidified peelable layer is sufficiently flexible andadhesive to the skin such that when applied to the skin at a humanjoint, the solidified peelable layer will remain substantially intact onthe skin upon bending of the joint.
 74. A method as in claim 56, whereinthe peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 2 hours following the formationof said solidified peelable layer.
 75. A method as in claim 56, whereinthe peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 4 hours following the formationof said solidified peelable layer.
 76. A method as in claim 56, whereinthe peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 8 hours following the formationof said solidified peelable layer.
 77. A method as in claim 56, whereinthe peelable formulation is configured to deliver the drug at asubstantially constant rate for at least 12 hours following theformation of said solidified peelable layer.
 78. A method as in claim56, wherein the weight ratio of the non-volatile solvent system to thepeel-forming agent is from about 0.01:1 to about 2:1.
 79. A method as inclaim 56, wherein the weight ratio of the non-volatile solvent system tothe peel-forming agent is from about 0.2:1 to about 1.2:1.
 80. A methodas in claim 56, wherein the solidified peelable layer is formed within15 minutes of the application to the skin surface.
 81. A method as inclaim 56, wherein the solidified peelable layer is formed within 4minutes of the application to the skin surface.
 82. A method as in claim56, wherein the formulation has an initial viscosity from about 100 toabout 3,000,000 centipoises.
 83. A method as in claim 56, wherein theformulation has an initial viscosity from about 1,000 to about 1,000,000centipoises.
 84. A method as in claim 56, wherein the step of applyingincludes applying the adhesive peelable formulation over an area of theskin surface that is sufficiently large to deliver a therapeuticallyeffective amount of the drug.
 85. A method of preparing an adhesivepeel-forming formulation for dermal drug delivery, comprising: a)selecting a drug suitable for dermal delivery; b) selecting non-volatilesolvent system consisting essentially of one non-volatile solvent thathas a solubility with respect to the drug within a window of operablesolubility; and c) formulating the drug and the non-volatile solventinto an adhesive peel-forming formulation that further includes apeel-forming agent and a volatile solvent system including at least onevolatile solvent, said adhesive peel-forming formulation having aviscosity suitable for application to a skin surface prior toevaporation of the volatile solvent system, and wherein the formulationapplied to the skin surface forms a solidified peelable layer after atleast a portion of the volatile solvent system is evaporated, andwherein the drug continues to be delivered at therapeutically effectiverates after the volatile solvent system is substantially evaporated. 86.A method as in claim 85, wherein the drug is selected from the groupconsisting of non-steroidal anti-inflammatory drugs (NSAIDs) includingketoprofen and diclofanec; COX-2 selective NSAIDs and agents; COX-3selective NSAIDs and agents; local anesthetics including lidocaine,bupivacaine, ropivacaine, and tetracaine; steroids includingdexamethasone; antibiotics, retinoids, clonidine, peroxides, retinol,salicylic acid, imiquimod, humectants, emollients, antiviral drugsincluding acyclovir, trifluridine, idoxuridine, penciclovir,famciclovir, cidofovir, gancyclovir, valacyclovir, acyclovir, podofilox,podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz,lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir,indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon,oseltamivir, ribavirin, rimantadine, zanamivir, and combinationsthereof; antifungal drugs including ciclopirox, imidazoles, miconazole,clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole and theallylamine derivatives such as butenafine, naftifine, and terbinafine,and combinations thereof.
 87. A method as in claim 85, wherein thenon-volatile solvent is selected from the group consisting of glycerol,polyethylene glycol having a weight average molecular weight from about200 MW to 800 MW, mineral oil, petrolatum, castor oil, n-methylpyrrolidone, vegetable oil, honey, oleyl alcohol, dipropylene glycol,polyoxyethylene derivative of sorbitan esters, saturated polyglycolyzedC₈ to C₁₀ glycerides, polyoxyethylated fatty acid glycerides,dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyl oleate,essential oils including eugenol and rose oil, oleic acid, oleylalcohol, isostearic acid, fatty acids and medium chain fatty acids. 88.A method of preparing an adhesive peel-forming formulation for dermaldrug delivery, comprising: a) selecting a drug suitable for dermaldelivery; b) forming a non-volatile solvent system by selecting at leasttwo non-volatile solvents according to a ratio that positions thesolubility of the drug in the non-volatile solvent system within awindow of operable solubility; and c) formulating the drug and thenon-volatile solvent system into an adhesive peel-forming formulationthat further includes a peel-forming agent and a volatile solvent systemincluding at least one volatile solvent, said adhesive peel-formingformulation having a viscosity suitable for application to a skinsurface prior to evaporation of the volatile solvent system, and whereinthe formulation applied to the skin surface forms a solidified peelablelayer after at least a portion of the volatile solvent system isevaporated, and wherein the drug continues to be delivered attherapeutically effective rates after the volatile solvent system issubstantially evaporated.
 89. A method as in claim 88, wherein the drugis selected from the group consisting of non-steroidal anti-inflammatorydrugs (NSAIDs) including ketoprofen and diclofanec; COX-2 selectiveNSAIDs and agents; COX-3 selective NSAIDs and agents; local anestheticsincluding lidocaine, bupivacaine, ropivacaine, and tetracaine; steroidsincluding dexamethasone; antibiotics, retinoids, clonidine, peroxides,retinol, salicylic acid, imiquimod, humectants, emollients, antiviraldrugs including acyclovir, penciclovir, famciclovir, valacyclovirsteroids, and behenyl alcohol; and combinations thereof.
 90. A method asin claim 88, wherein the non-volatile solvent system includes a memberselected from the group of glycerol, polyethylene glycol having a weightaverage molecular weight from about 200 MW to 800 MW, mineral oil,petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey,oleyl alcohol, dipropylene glycol, polyoxyethylene derivative ofsorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides,polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fattyalcohol, isopropyl myristate, ethyl oleate, essential oils includingeugenol and rose oil, oleic acid, isostearic acid, fatty acids andmedium chain fatty acids, and mixtures thereof.
 91. A method as in claim88, wherein at least one of the non-volatile solvents is added toimprove non-volatile solvent system compatibility with the peel-formingagent.
 92. A solidified peelable layer for delivering a drug,comprising: a) a drug; b) a non-volatile solvent system having one ormore non-volatile solvent, wherein the non-volatile solvent systemprovides a window of operable solubility for the drug such that the drugis deliverable at therapeutically effective rates for at least 2 hours;and c) a peel-forming agent, wherein said peelable layer can bestretched in at least one direction by 10% without breaking or cracking.93. A solidified peelable layer as in claim 92, wherein the non-volatilesolvent system acts as a plasticizer for the peel-forming agent.
 94. Asolidified peelable layer as in claim 92, wherein solidified peelablelayer is sufficiently adhesive and flexible to remain substantiallyintact on a skin surface adjacent to a joint or muscle group whereregular skin stretching occurs.
 95. A solidified peelable layer as inclaim 92, wherein the non-volatile solvent system includes multiplesolvents admixed together according to a ratio that positions thesolubility of the drug within a window of operable solubility withrespect to the non-volatile solvent system.
 96. A solidified peelablelayer as in claim 92, wherein the non-volatile solvent system includes amember selected from the group of glycerol, polyethylene glycol having aweight average molecular weight from about 200 MW to 800 MW, mineraloil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey,oleyl alcohol, dipropylene glycol, polyoxyethylene derivative ofsorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides,polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fattyalcohol, isopropyl myristate, ethyl oleate, essential oils includingeugenol and rose oil, oleic acid, isostearic acid, fatty acids andmedium chain fatty acids, and mixtures thereof.
 97. A solidifiedpeelable layer as in claim 92, wherein the peel-forming agent includesat a member selected from the group consisting of dextrin, guar gum,xantham gum, polyethylene oxide having a weight average molecular weightgreater than about 5,000 Mw, starch, cellulose derivatives,hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose,hydroxypropylcellulose, methyacrylic polymer, methyacrylic acid-ethylacrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer,polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin, dextrin,guar gum, xantham gum, polyethylene oxide, starch, cellulosederivatives, copolymers of methyl vinyl ether and maleic anhydride, andmixtures thereof.
 98. A solidified peelable layer as in claim 92,wherein the drug is selected from the group consisting of non-steroidalanti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;COX-2 selective NSAIDs and agents; COX-3 selective NSAIDs and agents;local anesthetics including lidocaine, bupivacaine, ropivacaine, andtetracaine; steroids including dexamethasone; antibiotics, retinoids,clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants,emollients, antiviral drugs including acyclovir, trifluridine,idoxuridine, penciclovir, famciclovir, Cidofovir, Gancyclovir,valacyclovir, podofilox, podophyllotoxin,ribavirin, Abacavir,Delavirdine, Didanosine, Efavirenz, Lamivudine, Nevirapine, Stavudine,Zalcitabine, Zidovudine, Amprenavir, Indinavir, Nelfinavir, Ritonavir,Saquinavir, Amantadine, Interferon, Oseltamivir, Ribavirin, Rimantadine,Zanamivir; antifungal drugs including ciclopirox, imidazoles,miconazole, clotrimazole, econazole, ketoconazole, oxiconazole,sulconazole and allylamine derivatives including butenafine, naftifine,and terbinafine; and combinations thereof.
 99. An adhesive peel-formingformulation for dermal delivery of a drug comprising: a) a drug; b) apeel-forming agent; and c) a solvent vehicle, comprising i) a volatilesolvent system including one or more volatile solvent, and ii) anon-volatile solvent system including one or more non-volatile solvent,wherein when said adhesive peel-forming formulation is applied to a skinsurface, the adhesive peel-forming formulation forms a solidifiedpeelable layer having a contact surface, said contact surface having afirst area dimension, said solidified peelable layer being stretchablesuch that the first area dimension is capable of being stretched to asecond area dimension that is 10% larger than the first area dimensionwithout cracking, breaking, or separating from the skin surface; andwherein after the formation of said solidified peelable layer and afterthe volatile solvent system is substantially evaporated the drugcontinues to be delivered at therapeutically effective rates.
 100. Aformulation as in claim 99, wherein said volatile solvent systemincludes a member selected from the group consisting of water, ethanol,isopropyl alcohol, ethyl acetate, acetone, and mixtures thereof.
 101. Aformulation as in claim 99, wherein the non-volatile solvent systemcomprises one or more solvents selected from the group consisting ofglycerol, polyethylene glycol having a weight average molecular weightfrom about 200 MW to 800 MW, mineral oil, petrolatum, castor oil,n-methyl pyrrolidone, vegetable oil, honey, oleyl alcohol, dipropyleneglycol, polyoxyethylene derivative of sorbitan esters, saturatedpolyglycolyzed C₈ to C₁₀ glycerides, polyoxyethylated fatty acidglycerides, dimethylsulfoxide, fatty alcohol, isopropyl myristate, ethyloleate, essential oils including eugenol and rose oil, oleic acid,isostearic acid, medium chain fatty acid and other fatty acids, andmixtures thereof.
 102. A formulation as in claim 99, wherein thepeel-forming agent includes a member selected from the group consistingof polyvinyl alcohol, polyvinyl pyrrolidone, carrageenin, gelatin,dextrin, guar gum, xantham gum, polyethylene oxide having a weightaverage molecular weight greater than about 5,000 Mw, starch, cellulosederivatives, and mixtures thereof.
 103. A formulation as in claim 99,wherein the drug is selected from the group consisting of non-steroidalanti-inflammatory drugs (NSAIDs) including ketoprofen and diclofanec;COX-2 selective NSAIDs and agents; COX-3 selective NSAIDs and agents;local anesthetics including lidocaine, bupivacaine, ropivacaine, andtetracaine; steroids including dexamethasone; antibiotics, retinoids,clonidine, peroxides, retinol, salicylic acid, imiquimod, humectants,emollients, antiviral drugs including acyclovir, trifluridine,idoxuridine, penciclovir, famciclovir, cidofovir, gancyclovir,valacyclovir, podofilox, podophyllotoxin,ribavirin, abacavir,delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine,zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir,saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine,and zanamivir; antifungal drugs including ciclopirox, imidazole,miconazole, clotrimazole, econazole, ketoconazole, oxiconazole,sulconazole and allylamine derivatives including butenafine, naftifine,and terbinafine; and combinations thereof.
 104. A formulation as inclaim 99, wherein the solidified peelable layer is sufficiently flexibleand adhesive to the skin such that when applied to the skin at a humanjoint, the solidified peelable layer will remain substantially intact onthe skin upon bending of the joint.
 105. A formulation as in claim 99,wherein the weight ratio of the non-volatile solvent system to thepeel-forming polymer is from about 0.01:1 to about 2:1.
 106. Aformulation as in claim 99, wherein the weight ratio of the non-volatilesolvent system to the peel-forming polymer from about 0.2:1 to about1.2:1.
 107. A formulation as in claim 99, wherein the solidifiedpeelable layer is formed within 15 minutes of the application to theskin surface under normal skin and ambient conditions.
 108. Aformulation as in claim 99, wherein the solidified peelable layer isformed within 4 minutes of the application to the skin surface.
 109. Anadhesive peel-forming formulation for dermal delivery of a drug,comprising: a) a drug selected from the group consisting ofnon-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen anddiclofanec; COX-2 selective NSAIDs and agents; COX-3 selective NSAIDsand agents; local anesthetics including lidocaine, bupivacaine,ropivacaine, and tetracaine; steroids including dexamethasone;antibiotics, retinoids, clonidine, peroxides, retinol, salicylic acid,imiquimod, humectants, emollients, antiviral drugs including acyclovir,trifluridine, idoxuridine, penciclovir, famciclovir, cidofovir,gancyclovir, valacyclovir, podofilox, podophyllotoxin,ribavirin,abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine,stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir,ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin,rimantadine, and zanamivir; antifungal drugs including ciclopirox,imidazole, miconazole, clotrimazole, econazole, ketoconazole,oxiconazole, sulconazole and allylamine derivatives includingbutenafine, naftifine, and terbinafine; and combinations thereof; b) asolvent vehicle, comprising: i) a volatile solvent system including oneor more volatile solvent selected from the group of water, ethanol,isopropyl alcohol, ethyl acetate, acetone, mixtures thereof, and ii) anon-volatile solvent system including one or more non-volatile solvent,wherein the non-volatile solvent system has a solubility with respect tothe drug that is within a window of operable solubility such that thedrug is deliverable at therapeutically effective rates over a sustainedperiod of time; and said one or more non-volatile solvent is selectedfrom the group consisting of glycerol, polyethylene glycol having aweight average molecular weight from about 200 MW to 800 MW, mineraloil, petrolatum, castor oil, n-methyl pyrrolidone, vegetable oil, honey,oleyl alcohol, dipropylene glycol, polyoxyethylene derivative ofsorbitan esters, saturated polyglycolyzed C₈ to C₁₀ glycerides,polyoxyethylated fatty acid glycerides, dimethylsulfoxide, fattyalcohol, isopropyl myristate, ethyl oleate, essential oils includingeugenol and rose oil, oleic acid, oleyl alcohol, isostearic acid, fattyacids including medium chain fatty acids, and mixtures thereof; and c) apeel-forming agent, selected from the group consisting of polyvinylalcohol, polyvinyl pyrrolidone, carrageenin, gelatin, dextrin, guar gum,xantham gum, polyethylene oxide, hydroxyethylcellulose, ehtylcellulose,carboxymethylcellulose, hydroxypropylcellulose, copolymers of methylvinyl ether and maleic anhydride, polyvinyl alcohol-polyethylene glycolco-polymers, methacrylic acid and methacrylate-based copolymersincluding poly(methacrylic acid) copolymers, methylmethacrylatecopolymers, methyacrylic acid-ethyl acrylate copolymers; wherein theformulation has a viscosity suitable for application and adhesion to askin surface prior to evaporation of the volatile solvent system, andwherein the formulation applied to the skin surface forms a solidifiedpeelable layer after at least partial evaporation of the volatilesolvent system, wherein the drug continues to be delivered after thevolatile solvent system is substantially evaporated, wherein theformulation has a drying time of 5 minutes or shorter under standardskin and ambient conditions, wherein the weight ratio of thenon-volatile solvent system to the peel-forming polymer is from about0.2:1 to about 1.2:1, and wherein the solidified peelable layer can bestretched in at least one direction by 10% without cracking, breaking,or separating from the skin.